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ZC3H12D Is a Prognostic Biomarker Associated with Immune Cell Infiltration in Lung Adenocarcinoma

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6142 Original Article ZC3H12D is a prognostic biomarker associated with immune cell infiltration in lung adenocarcinoma Wangang Gong1,2,3, Wumin Dai1,2,3, Haibin Wei1,2,3, Yongyi Chen1,2,3, Zhiguo Zheng1,2,3 1Institute of Cancer and Basic Medical (ICBM), Chinese Academy of Sciences, Hangzhou, China; 2Zhejiang Cancer Research Institute, Cancer Hospital of University of Chinese Academy of Sciences, Hangzhou, China; 3Zhejiang Cancer Research Institute, Zhejiang Cancer Hospital, Hangzhou, China Contributions: (I) Conception and design: Z Zheng; (II) Administrative support: Z Zheng; (III) Provision of study materials or patients: W Dai, Y Chen; (IV) Collection and assembly of data: W Gong, H Wei; (V) Data analysis and interpretation: W Gong; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Zhiguo Zheng, PhD. Zhejiang Cancer Research Institute, Zhejiang Cancer Hospital, 1# Banshan Road, Hangzhou 310022, China. Email: [email protected]. Background: ZC3H12 family members have an important role in tumorigenesis and development. However, the relationship between ZC3H12 family members and the prognosis of lung adenocarcinoma (LUAD) and tumor infiltrating lymphocytes is not clear. Methods: The expression of ZC3H12 family members in LUAD was analyzed by UALCAN. UALCAN, Kaplan–Meier Plotter, and GEPIA were used to evaluate the effect of ZC3H12 family members on the prognosis of LUAD. The relationship between prognostic ZC3H12 family members and 14 functional states of LUAD was studied by CancerSEA. The correlation between ZC3H12 and immune cell infiltration was studied by TIMMER. In addition, the correlation between ZC3H12D expression and an immune infiltration gene marker set was analyzed by TISIDB and GEPIA. Finally, the expression of ZC3H12D in LUAD was further verified by the GEO database and immunohistochemical staining. Results: The combined prognostic analysis of UALCAN, Kaplan-Meier Plotter, and GEPIA showed that the up-regulated expression of ZC3H12D mRNA was closely related to an improvement in overall survival rate (OS) in patients with LUAD. There was no significant correlation between ZC3H12D and 14 functional states of LUAD. Further analysis showed that the expression of ZC3H12D was positively correlated with the infiltration of B cells and CD4+T cells in LUAD. The expression of ZC3H12D was also positively correlated with immune markers in LUAD, including B cell-derived TNF and LTA cytokines, CXCL13, and its receptor CXCR5. Immunohistochemical staining showed that the expression of ZC3H12D in LUAD tissue samples was higher than normal lung tissues. Conclusions: These findings suggest that multiple ZC3H12 family members are associated with the prognosis of patients with LUAD tumors. The increased expression of ZC3H12D was correlated with improved prognosis. ZC3H12D was shown to be associated with the level of immune cell infiltration, including B cells and CD4+T cells. Thus, ZC3H12D can be used as a biomarker to judge the prognosis and immune infiltration of LUAD. Keywords: Bioinformatics analysis; lung adenocarcinoma (LUAD); infiltration of immune cells; ZC3H12D Submitted Mar 12, 2020. Accepted for publication Aug 05, 2020. doi: 10.21037/tcr-20-1465 View this article at: http://dx.doi.org/10.21037/tcr-20-1465 © Translational Cancer Research. All rights reserved. Transl Cancer Res 2020;9(10):6128-6142 | http://dx.doi.org/10.21037/tcr-20-1465 Translational Cancer Research, Vol 9, No 10 October 2020 6129 Introduction carcinoma have a good prognosis (14). Interestingly, members of the ZC3H12 family also provide a local Primary lung cancer is one of the malignancies associated inflammatory environment for tumor development. For with the highest morbidity and mortality worldwide, example, ZC3H12A degrades transcripts of angiogenic especially in China (1). Non-small cell lung cancer factors secreted by cells (VEGF, IL-8, and IL-6) and (NSCLC) is the main pathologic type of lung cancer, downregulation of ZC3H12A induces tumor angiogenesis accounting for approximately 80% of all lung cancers. in renal cell carcinoma endothelial cells (8). Recently, Lung adenocarcinoma (LUAD) is the most common form ZC3H12D has been considered to be a new negative of NSCLC, accounting for more than 50% of cases (2). feedback regulator of Toll-like receptor (TLR) signaling The prognosis of LUAD is poor, with a 5-year survival and macrophage activation. Overexpression of ZC3H12D rate of 4–17% (3). Immunotherapy is a new method for significantly inhibits JNK, ERK, and NF-κB signal the treatment of LUAD, and has achieved unprecedented transduction and macrophage inflammation induced by results in patients with advanced LUAD. However, there TLR2 and TLR4 activation (13). However, the mechanism is a wide range of challenges in clinical application, such as of ZC3H12 family members in LUAD progression and the lack of biomarkers that can effectively predict efficacy, tumor immunology has not been established. prognosis, and treatment-related adverse reactions (4). In this study we used multiple databases to analyze the In addition, a number of studies have shown that tumor- level of expression and prognosis of different ZC3H12 infiltrating lymphocytes, such as tumor-associated macrophages family proteins in patients with LUAD. We also used the (TAM) and tumor-infiltrating neutrophils (TINs), affect the tumor immune research evaluation resource (TIMER) to prognosis and efficacy of immunotherapy (5). Therefore, analyze the correlation between ZC3H12D and LUAD the identification of prognostic biomarkers and new immune cell infiltration to determine the prognostic value immune-related therapeutic targets has enormous potential of ZC3H12D in LUAD and its interaction with tumor in the treatment for LUAD. immune potential. ZC3H12 is a newly discovered zinc finger protein family of the CCCH type, which consists of four ZC3H12A-D members (6). The ZC3H12 protein family, also known Methods as MCPIP, is an endonuclease that degrades mRNA UALCAN data analysis transcripts by recognizing the stem-loop structure at the end of mRNA 3'UTR (7). ZC3H12 family proteins UALCAN (http://ualcan.path.uab.edu) is an easy-to-use are abnormally expressed in a variety of tumors, and interactive portal for in-depth analysis of TCGA gene participate in the development and progression of tumors, expression data. UALCAN can be used to analyze the thus affecting the prognosis. It has been reported that the relative expression of genes in different tumor types and expression of ZC3H12A is down-regulated in breast cancer, grades, and to evaluate the impact of gene expression and neuroblastomas, and renal clear cell carcinomas, and low clinicopathologic features on patient survival. In addition, expression of ZC3H12A is related to tumor grade and poor additional information about the selected gene/target is prognosis for breast cancer (8,9). Studies have shown that provided through connection with HPRD, GeneCards, the expression of ZC3H12C in colon cancer is lower than Pubmed, TargetScan, Human protein atlas, DRUGBANK, normal colon tissues, while overexpression of ZC3H12C Open targets and GTEx. In this study, UALCAN inhibits the migration of colon cancer cells (10). ZC3H12D database was used for the analysis of the expression of was originally considered to be a tumor suppressor, and ZC3H12 family genes in primary LUAD patients and the has also been referred to as p34, MCPIP4, and TFL (11). investigation of the correlation between the ZC3H12 family Recent studies have shown that ZC3H12D reduces the members and the survival of patients. global ubiquitin of cellular proteins, and polyubiquitin plays a key role in promoting the tumor cell proliferation and Kaplan-Meier plotter database analysis survival signal pathway (12,13). It has also been reported that ZC3H12D is highly expressed in human endometrial Kaplan-Meier Plotter analysis was used to assess how carcinoma, but not expressed or weakly expressed in normal 10,461 cancer samples impacted 54,675 genes on survival. tissues, the patients with high expression of endometrial These samples included 5,143 breast, 1,816 ovarian, 2,437 © Translational Cancer Research. All rights reserved. Transl Cancer Res 2020;9(10):6128-6142 | http://dx.doi.org/10.21037/tcr-20-1465 6130 Gong et al. ZC3H12D is a prognostic biomarker in LUAD lung, and 1,065 gastric cancer samples on the HGU133 cistrome.shinyapps.io/timer/). TIMER used the previously Plus 2.0 array. The average follow-up time was 69, 40, 49 published deconvolution statistical method to infer the and 33 months, respectively (15). Kaplan-Meier Plotter abundance of tumor-infiltrating immune cells from gene (http://kmplot.com/analysis/) was used to analyze the expression profiles. The TIMER database included 10,897 relationship between the expression of ZC3H12 family samples from 32 cancer types from The Cancer Genome genes and the survival of LUAD. The hazard ratio (HR) Atlas (TCGA) to estimate the abundance of immune with 95% confidence intervals and log-rank P-value were infiltration. We analyzed the correlation between the also computed. expression of ZC3H12 family genes and the abundance of immune infiltrating cells (including B cells, CD4+T cells, CD8+T cells, neutrophils, macrophages, and dendritic GEPIA was used to verify the correlation between ZC3H12 cells) through a gene module. Gene expression against family genes and LUAD survival tumor purity is displayed on the left-most panel (18). In Gene Expression Profiling Interactive Analysis
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